You DO NOT need to be part of the NeuroNEXT infrastructure to apply to conduct a study within the network. Applications from academic
investigators, advocacy groups/foundations, small businesses and the pharmaceutical industry are welcomed.

NeuroNEXT is intended to facilitate the testing of novel therapeutics (drugs, biologics, devices) for neurological disorders.
These novel therapeutics may come from academic investigators or directly from the biotechnology or pharmaceutical sector.
NeuroNEXT aims to support scientifically sound phase 2 clinical trials that provide data for clear go/no-go decisions. Biomarker
validation studies are also considered either independently or as part of a therapeutic trial.

Working with NeuroNEXT is a cooperative venture between NINDS, the NeuroNEXT network and the applicant. NINDS will provide
guidance to potential applicants with input from the Office of Clinical Research (OCR), the applicable NINDS Extramural office/cluster
and the NeuroNEXT Executive Committee (NEC). Potential applicants should contact NINDS OCR in order to discuss the feasibility
of conducting the proposed trial through the NeuroNEXT infrastructure.

Industry may apply for expedited access to NeuroNEXT expertise and infrastructure through the NeuroNEXT Infrastructure Resource Access (X01) (PAR-11-344) under a cost-sharing arrangement and Cooperative Research and Development Agreement (CRADA) with NINDS.

Small businesses may apply for cooperative agreement grants: NeuroNEXT Clinical Trials (U01) (PAR-11-343); OR through our Small Business program: NeuroNEXT Small Business Innovation in Clinical Trials (U44) (PAR-11-345).

NINDS program staff, including the Office/Cluster which holds the disease of interest within its portfolio, will discuss the
proposed trial

Trials which have good NINDS program support are referred to the NEC to assess network feasibility

Projects which have NINDS program support and are feasible for network performance are asked to submit a formal application
for peer review by the NeuroNEXT SEP and subsequent consideration by the NINDS Advisory Council. The NeuroNEXT CCC will assist
in protocol development in support of the formal application.

Multiple Sclerosis (MS) is a chronic, inflammatory demyelinating disease of the central nervous system that affects 400,000
people in the US and 2 million people worldwide. Those affected with the disease are characterized by their progression into
one of three variants: relapsing-remitting, secondary-progressive and primary-progressive. Despite recent improvements in
pharmacotherapy for relapsing-remitting Multiple Sclerosis (RRMS), there are no therapies with demonstrated efficacy in progressive
Multiple Sclerosis in the absence of relapses.

We are doing this research study to determine the safety, tolerability and activity of ibudilast (MN-166) administered twice
daily over a 96 week period in subjects with primary and secondary-progressive multiple sclerosis. The study will be conducted
by the NIH-funded NeuroNEXT Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) in NeuroNEXT sites around the
United States. A total of 250 male and female subjects from 21 to 65 years old, inclusive, are planned to be enrolled into
2 treatment arms (ibudilast or matching-placebo). The trial will utilize advanced brain imaging to assess activity and correlate
clinical activity with these imaging measures.

This study is also being supported by Medicinova and the National Multiple Sclerosis Society as part of a private-public partnership
with the NIH.

Myasthenia gravis (MG) is an autoimmune disorder of neuromuscular transmission with an estimated annual incidence of about
1-2 per 100,000 and prevalence as high as 20-50 per 100,000. Despite current therapies a subset of patients remain medically
refractory or have intolerable medication adverse effects. There is need for another agent in the management of MG as there
are few effective drugs. Safe, well-tolerated, effective and steroid-sparing therapeutics are very desirable.

The purpose of the study is to find out the effect and safety of a new use of the drug rituximab in myasthenia gravis (MG)
patients who are on prednisone.

NN-104 StrokePatrick D. Lyden, MD, Chairman of the Department of Neurology at Cedars-Sinai Medical Center, is the Protocol Principal Investigator
of the study "Safety evaluation of 3K3A-APC in ischemic stroke" (NN104). Kent E. Pryor, PhD, Chief Operating Officer of ZZ
Biotech, is the Principal Investigator of the X01 NeuroNEXT Infrastructure Resource Access Award. Berislav V. Zlokovic, MD,
PhD, Director of the Zilkha Neurogenetic Institute at Keck School of Medicine, University of Southern California, is the Co-Investigator.

Currently, the only approved treatment in the US for ischemic stroke is a drug called recombinant tissue plasminogen activator
(rtPA or tPA), indicated for intravenous administration within three hours of onset of the stroke. The drug is designed to
break down blood clots to restore blood flow to the brain and thereby prevent further damage. In some patients however, tPA
can cause internal bleeding and other complications. 3K3A-APC’s cytoprotective properties may be useful in protecting ischemic
brain tissue from further damage, while avoiding an increase in the chance of treatment-related bleeding.

This research study is being conducted to determine the safety, tolerability and activity of 3K3A-APC, following the use of
tissue plasminogen activator (tPA) in subjects who have experienced moderately severe acute hemispheric ischemic stroke. The
study intervention will be administered as a 15 minute infusion every 12 hours for up to 5 infusions. Four dose levels will
be considered for this trial. Approximately one hundred participants of age 18-80 years old will be enrolled and followed
for 90 days.